A number of polypeptides having smooth muscle relaxant activity have been discovered. VIP (vasoactive intestinal polypeptide) is an example of such polypeptides. VIP is a peptide hormone that was purified from a side fraction in the extraction and purification of secretin from porcine duodenum in 1970 by Said and Mutt. The primary amino acid structure of VIP, which was clarified in 1974 (Eur. J. Biochem., vol. 42, pp. 581-589 (1974)), is as follows (SEQ ID NO: 1): ##STR1## Since this amino acid structure is similar to those of secretin and glucagon, VIP is considered to be a peptide hormone belonging to the glucagon-secretin family.
VIP occurs widely in the nervous system, as well as in the digestive tract, and has various biological activities. It is clear that VIP has strong vasodilating and hypotensive activity, smooth muscle relaxant activity, intestinal juice secretion promoting activity, pancreatic juice and bile secretion promoting activity, gastric juice secretion suppressing activity, and glycogenolitic promoting activity. Although the presence of VIP in the lungs of normal subjects has been confirmed, this polypeptide has never been found in patients with bronchial asthma (N. Eng. J. Med., vol. 320, pp. 1244-1248 (1989)).
Based on these facts, it is expected that VIP is applicable to the treatment of, in particular, bronchial asthma from among the various actions as described above. In fact, it is reported that the administration of natural type VIP, which has the amino acid sequence of human VIP, to man exhibits, although slightly, a suppressive effect on tracheostenosis induced by histamine (Pharmacologist, vol. 25, pp. 123 (1983); and Am. Rev. Respir. Dis, vol. 130, pp. 162-166 (1984)).
Natural type VIP, however, is highly unstable under the conditions usually employed for storing drugs. Furthermore, it has been demonstrated that when natural VIP is administered into, for example, the respiratory tract, it is easily degraded by protease. It is reported that, when natural type VIP is incubated together with enkephalinase, which is an enzyme frequently observed on the respiratory tract mucosa, in an in vitro test, more than 70% of the VIP is degraded within 15 minutes (Biochem. Biophys. Res. Commun., vol. 158, pp. 850-854 (1989)). It is also reported that when VIP is treated with a broncho-alveolar lavage wash from guinea pig at 37.degree. C., the half-life of VIP is about 1.5 hours (Biomedical Res., vol. 13, Supplement 2, pp. 25-30 (1992)).
Workers at the Applicants' company have previously found that a compound having an amino acid residue other than a methionine residue at the 17-position and a homoserine residue (Hse, including homoserine lactone residues) at the C-terminal as well as an amide derivative and a higher fatty acid amide derivative thereof show VIP-like physiological activities (JP-A-4-59794 and EP-A-0,463,450; the term "JP-A" as used herein means an "unexamined published Japanese patent application"). They have further attempted to blend surfactants with such VIP analogs to improve absorption properties, and to blend peptidase inhibitors therewith to improve stability (JP-A-5-238950).
However, the polypeptide compounds and modified polypeptide compounds disclosed in these publications demonstrate poor solution stability in high concentrations, because they have an aspartic acid residue and an asparagine residue, which are likely to undergo rearrangement reactions at the 8- and 24-positions, respectively.
Accordingly, the workers at the Applicants' company have conducted extensive studies in order to develop VIP analogs having high VIP-like physiological activities and improved stability. Specifically, they have designed and synthesized novel amino acid sequences by replacing amino acids that seem to cause the unstable properties of [Leu.sup.7 ]-VIP-Hse (i.e., a peptide derived from VIP by replacing the amino acid reside at the 17th position to Leu and adding Hse at the C-terminus) with stable ones occurring in nature, and have examined the stabilities and activities of the products in solutions. As a result, they have successfully discovered that the new VIP analogs have highly improved storage stabilities and extremely high activities (JP-A-6-220090 corresponding to EP-A-0,613,904).
Besides being easily degraded in the respiratory tract, the use of VIP is also disadvantageous because it must be repeatedly administered in large doses to achieve a sufficient medical effect and, further, because it is hardly absorbed via the respiratory tract mucosa due to its high molecular weight.
Accordingly, an object of the present invention is to provide a modified polypeptide compound that is designed to have excellent stability in vivo and persistent action, by chemically modifying the VIP analogs disclosed in the above-mentioned JP-A-6-220090 corresponding to EP-A-0,613,904, which are superior to conventional VIP analogs in stability in an aqueous solution and in VIP-like activities.